CN102050815B - Dabigatran ester derivatives as prodrug - Google Patents
Dabigatran ester derivatives as prodrug Download PDFInfo
- Publication number
- CN102050815B CN102050815B CN200910211165.2A CN200910211165A CN102050815B CN 102050815 B CN102050815 B CN 102050815B CN 200910211165 A CN200910211165 A CN 200910211165A CN 102050815 B CN102050815 B CN 102050815B
- Authority
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- China
- Prior art keywords
- methyl
- dabigatran
- amino
- ester
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960003850 dabigatran Drugs 0.000 title claims abstract description 48
- -1 Dabigatran ester Chemical class 0.000 title abstract description 35
- 229940002612 prodrug Drugs 0.000 title description 2
- 239000000651 prodrug Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 229940122388 Thrombin inhibitor Drugs 0.000 claims abstract description 7
- 239000003868 thrombin inhibitor Substances 0.000 claims abstract description 7
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims description 41
- 150000002148 esters Chemical class 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 abstract description 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 239000002131 composite material Substances 0.000 abstract 2
- 231100000252 nontoxic Toxicity 0.000 abstract 1
- 230000003000 nontoxic effect Effects 0.000 abstract 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 38
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
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- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 14
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- 229940000635 beta-alanine Drugs 0.000 description 10
- BGLLICFSSKPUMR-UHFFFAOYSA-N ethyl 3-[[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoate Chemical compound C=1C=CC=NC=1N(CCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CNC1=CC=C(C(N)=N)C=C1 BGLLICFSSKPUMR-UHFFFAOYSA-N 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229960000288 dabigatran etexilate Drugs 0.000 description 5
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 5
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- 239000001301 oxygen Substances 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- FRKPLOTVTBSTPB-UHFFFAOYSA-N ClS(=O)(=O)O.ClC(=O)O Chemical class ClS(=O)(=O)O.ClC(=O)O FRKPLOTVTBSTPB-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- VRIGUKQJHAWXGW-IUCAKERBSA-N chloromethyl (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate Chemical compound ClCOC(=O)[C@H]([C@@H](C)CC)NC(=O)OC(C)(C)C VRIGUKQJHAWXGW-IUCAKERBSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
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- 230000002496 gastric effect Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 2
- FTINTRPSAYYLMB-UHFFFAOYSA-N 2-amino-4-methyl-3-nitrobenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(N)=C1[N+]([O-])=O FTINTRPSAYYLMB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
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- 125000004103 aminoalkyl group Chemical group 0.000 description 2
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- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- UITNIDFEANEWPC-UHFFFAOYSA-N ethyl 3-(pyridin-2-ylamino)propanoate Chemical compound CCOC(=O)CCNC1=CC=CC=N1 UITNIDFEANEWPC-UHFFFAOYSA-N 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to dabigatran ester derivatives as shown in a constitutional formula I, pharmaceutically acceptable nontoxic salts thereof, medical composite containing the compounds as active components, and application of thrombin inhibitor of the compounds and medical composites, wherein R1 represents H or C1 to C5 alkyl; R2 represents H, or C1 to C3 alkyl; and R3 represents C1 to C8 alkyl or substituted alkyl.
Description
Technical field
The present invention relates to ester derivative and the non-toxicity pharmacy acceptable salt thereof of new dabigatran, and contain these compounds as the pharmaceutical composition of activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Background technology
Dabigatran (Dabigatran) is a kind of optionally high performance thrombin inhibitor.But due to the existence of strong basicity amidino groups, oral can not absorption.For improving its bioavailability, respectively the free carboxy in dabigatran molecule is become to ethyl ester, amidino groups becomes amino hexyl formate, obtains its bi precursor medicine dabigatran dibasic acid esters (Dabigatran Etexilate).After dabigatran dibasic acid esters is oral, from gastrointestinal absorption, be then converted in vivo the dabigatran of activity form, performance blood coagulation resisting function.Dabigatran dibasic acid esters, in listing in 2008, becomes first oral thrombin inhibitors, for deep vein thrombosis after preventing artificial joint replacement, forms and pulmonary embolism.But the oral administration biaavailability of dabigatran dibasic acid esters (6.5%) still needs further to be improved.
Dabigatran dabigatran dibasic acid esters
Summary of the invention
The present invention relates to ester derivative and non-toxicity pharmacy acceptable salt thereof by the dabigatran shown in structural formula I, and contain these compounds as the pharmaceutical composition of activeconstituents, and described compound and pharmaceutical composition are as the purposes of thrombin inhibitors.
Therefore, first aspect of the present invention provides ester derivative and the pharmacologically acceptable salt thereof of the dabigatran of formula I representative:
Wherein,
R
1represent H or C
1-C
5alkyl; R
2represent H, or C
1-C
3alkyl;
R
3represent C
1-C
8alkyl or substituted alkyl.
Preferably, the invention provides ester derivative or its pharmacologically acceptable salt, the wherein R of the dabigatran of formula I representative
1represent C
1-C
5alkyl, R
2represent H or C
1-C
3alkyl, R
3represent C
1-C
8alkyl.
More preferably, the invention provides ester derivative or its pharmacologically acceptable salt, the wherein R of the dabigatran of formula I representative
1represent C
1-C
5alkyl, R
2represent H, R
3represent that alpha-position is amino alkyl or the aromatic alkyl replacing.
More preferably, the invention provides the ester derivative of dabigatran of formula I representative or the compound that its pharmacologically acceptable salt is selected from following structural formula representative:
Each substituting group of objectives compound is defined as follows respectively:
I
1: R
1for-CH
3, R
2for H, R
3for-CH
3;
I
2: R
1for-CH
3, R
2for H, R
3for-CH
2cH
3;
I
3: R
1for-CH
3, R
2for H, R
3for-CH
2cH
2cH
3;
I
4: R
1for-CH
3, R
2for H, R
3for-CH (CH
3)
2;
I
5: R
1for-CH
3, R
2for H, R
3for-C (CH
3)
3;
I
6: R
1for-CH
3, R
2for H, R
3for-CH (CH
3) CH
2cH
3;
I
7: R
1for-CH
3, R
2for H, R
3for-CH
2cH (CH
3) CH
3;
I
8: R
1for-CH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
3;
I
9: R
1for-CH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
10: R
1for-CH
3, R
2for H, R
3for-CH
2nH
2;
I
11: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
12: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
13: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
14: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
15: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH
2ph;
I
16: R
1for-CH
3, R
2for H, R
3for
I
17: R
1for-CH
2cH
3, R
2for H, R
3for-CH
3;
I
18: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
3;
I
19: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
3;
I
20: R
1for-CH
2cH
3, R
2for H, R
3for-CH (CH
3)
2;
I
21: R
1for-CH
2cH
3, R
2for H, R
3for-C (CH
3)
3;
I
22: R
1for-CH
2cH
3, R
2for H, R
3for-CH (CH
3) CH
2cH
3;
I
23: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH (CH
3) CH
3;
I
24: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
3;
I
25: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
26: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2nH
2;
I
27: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
28: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
29: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
30: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
31: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2ph;
I
32: R
1for-CH
2cH
3, R
2for H, R
3for
I
33: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
3;
I
34: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2cH
3;
I
35: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
3;
I
36: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (CH
3)
2;
I
37: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-C (CH
3)
3;
I
38: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (CH
3) CH
2cH
3;
I
39: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2cH (CH
3) CH
3;
I
40: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
3;
I
41: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
42: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH
2nH
2;
I
43: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
44: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
45: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
46: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
47: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2ph;
I
48: R
1for-CH
2cH
2cH
3, R
2for H, R
3for H, R
3for
I
49: R
1for-CH
3, R
2for CH
3, R
3for-CH
3;
I
50: R
1for-CH
3, R
2for CH
3, R
3for-CH
2cH
3;
I
51: R
1for-CH
3, R
2for CH
3, R
3for-CH
2cH
2cH
3;
I
52: R
1for-CH
3, R
2for CH
3, R
3for-CH (CH
3)
2;
I
53: R
1for-CH
3, R
2for CH
3, R
3for-C (CH
3)
3;
I
54: R
1for-CH
3, R
2for CH
3, R
3for-CH (CH
3) CH
2cH
3;
I
55: R
1for-CH
3, R
2for CH
3, R
3for-CH
2cH (CH
3) CH
3;
I
56: R
1for-CH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
3;
I
57: R
1for-CH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
58: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
3;
I
66: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH
3;
I
67: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
3;
I
68: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH (CH
3)
2;
I
69: R
1for-CH
2cH
3, R
2for CH
3, R
3for-C (CH
3)
3;
I
70: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH (CH
3) CH
2cH
3;
I
71: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH (CH
3) CH
3;
I
72: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
3;
I
73: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
2cH
3;
I
74: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
3;
I
75: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
2cH
3;
I
76: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
3;
I
77: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH (CH
3)
2;
I
78: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-C (CH
3)
3;
I
79: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH (CH
3) CH
2cH
3;
I
80: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
2cH (CH
3) CH
3;
I
81: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
3;
I
82: R
1for-CH
2cH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
2cH
2cH
3.
Second aspect of the present invention relates to pharmaceutical composition, and it comprises ester derivative and pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier or the vehicle of the dabigatran of at least one formula I representative.
The 3rd aspect of the present invention relates to ester derivative and the non-toxicity pharmacy acceptable salt thereof of the dabigatran shown in formula I, and the ester derivative that comprises the dabigatran shown in formula I and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents the purposes as anticoagulation.
The compound of formula I representative can form pharmaceutical salts with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts with organic acid, such as acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.Selecting and preparing suitable salt is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can form solvate, such as hydrate, alcohol adduct etc.; Selecting and preparing suitable solvate is technology as well known to those skilled in the art.
The compounds of this invention or its pharmacologically acceptable salt can be separately or with the form administration of pharmaceutical composition.Pharmaceutical composition of the present invention can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they are conducive to active compound to be processed into the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can manufacture according to general knowledge well known in the art.
Route of administration can be oral, non-enteron aisle or topical, preferred oral and injection form administration.Can comprise capsule and tablet etc. by oral pharmaceutical preparation.Patient swallows while having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.The compounds of this invention also can be prepared for administered parenterally or transdermal administration or mucosal.Or adopt the mode administration of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system (DDS) to obtain more favourable effect.
It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.
Embodiment
The following examples can conduct further description the present invention, yet these embodiment should be as the restriction to scope of the present invention.
First, reference literature (Hauel NH, Nar H, Priepke H, et al.Structure-Based Designof Novel Potent Nonpeptide Thrombin Inhibitors.J.Med.Chem.2002; 45:1757-1766) the ethyl ester derivative of the dabigatran shown in the synthetic dabigatran dibasic acid esters (Dabigatran Etexilate) of method and formula II:
R
1=-CH
3,-(CH
2)
2cH
3,-(CH
2)
3cH
3, or-(CH
2)
4cH
3
The 3-nitro-4-methyl amino-phenylformic acid of take is starting raw material, reacts with sulfur oxychloride, becomes acyl chlorides (intermediate 2); Intermediate 2 reacts with N-(pyridine-2-yl)-Beta-alanine ethyl ester, obtains intermediate 4; By the nitro of intermediate 4, under the effect of palladium-charcoal, catalytic hydrogenation obtains intermediate 5; (4-cyano group-phenyl amino) acetic acid first reacts with carbonyl dimidazoles, then reacts with intermediate 5, obtains intermediate 7; By intermediate 7 and hcl reaction, then with volatile salt alkalization, obtain the ethyl ester derivative (II of dabigatran
1), II
1react with the own ester of chloroformic acid, obtain dabigatran dibasic acid esters (Dabigatran Etexilate); Intermediate 7 reacts with sodium hydroxide, and hydrolysis obtains carboxylic acid sodium derivative (intermediate 8); Intermediate 8 reacts with haloalkane, obtains ester derivative (intermediate 9); Intermediate 9 and hcl reaction, obtain the carboxylates derivatives II of dabigatran
2-5).
Reference example 1 N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (II
1) preparation
40 grams of (0.2mol) 3-nitro-4-methyl amino-phenylformic acid are added in 400mL sulfur oxychloride, add 0.2mL dimethyl formamide, back flow reaction 0.5h, vacuum concentration, obtain 3-nitro-4-methyl amino-Benzoyl chloride (intermediate 2), be dissolved in 300mL tetrahydrofuran (THF).
37 grams of (0.2mol) N-(pyridine-2-yl)-Beta-alanine ethyl ester and 60mL triethylamine are dissolved in 500mL tetrahydrofuran (THF), at room temperature drip the tetrahydrofuran solution of intermediate 2.After adding, room temperature reaction spends the night, vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of ethanol (99: 1), obtains 41 grams of intermediates 4.
33.4 grams of (89.4mmol) intermediates 4 are dissolved in to 400mL ethanol, add 1 gram of palladium-charcoal of 10%, room temperature hydrogenation, removes by filter palladium-charcoal, by filtrate vacuum concentration.Residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (30: 1), obtains 21 grams of intermediates 5.
12.8g (73mmol) (4-cyano group-phenyl amino) acetic acid and 11.8 grams of (73mmol) carbonyl dimidazoles are added in 300mL tetrahydrofuran (THF) to 50 ℃ of stirring reaction 30min.Then, in this solution, add 21 grams of intermediates 5, back flow reaction 24h.Vacuum concentration, is dissolved in residue in 150mL glacial acetic acid, and reflux 1h, by 500mL water dilution for this solution, neutralizes with strong aqua.By ethyl acetate, extract, by extracting solution vacuum concentration.Residue is separated with silica gel column chromatography, with methylene dichloride: the mixed solvent wash-out of methyl alcohol (40: 1), obtains 18 grams of N-{[2-(((4-cyano group-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (intermediate 7).
18 grams of intermediates 7 are dissolved in 800mL ethanol, are cooled to 0 ℃, logical anhydrous hydrogen chloride gas 2h, then stirring at room 5h.By solvent evaporated in vacuo, then residue is dissolved in to 600mL ethanol, add 40 grams of volatile salts, stirred overnight at room temperature.By reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1), obtains 14 grams of target compound II
1.
1H?NMRδ(ppm，DMSO-d
6)：1.14(t，3H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.42(dd，1H)，8.55-9.28(bs，3H)。
Reference example 2 N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (II
2) preparation
5 grams of intermediates 7 are dissolved in 200mL ethanol, add the NaOH solution 10.4mL of 1N, under room temperature, stirring reaction is complete to hydrolysis; Then evaporated in vacuo, with 20mL dimethyl formamide, dissolve, add 1.76 grams of methyl iodide, stirring at room 24h, vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (40: 1), obtains 3.9 grams of N-{[2-(((4-cyano group-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (intermediate 9a).
3.9 grams of intermediate 9a are dissolved in 100mL ethanol, are cooled to 0 ℃, logical anhydrous hydrogen chloride gas 2h, then stirring at room 5h.By solvent evaporated in vacuo, then residue is dissolved in to 100mL ethanol, add 10 grams of volatile salts, stirred overnight at room temperature.By reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1), obtains 2.7 grams of target compound II
2.
1H?NMRδ(ppm，DMSO-d
6)：2.68(t，2H)，3.79(s，3H)，3.86(s，3H)，4.25(t，2H)，4.69(d，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.42(dd，1H)，8.55-9.28(bs，3H)。
Reference example 3 N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (II
3) preparation
5 grams of intermediates 7 are dissolved in 200mL ethanol, add the NaOH solution 10.4mL of 1N, under room temperature, stirring reaction is complete to hydrolysis; Then evaporated in vacuo, with 20mL dimethyl formamide, dissolve, add 1.53 grams of N-PROPYLE BROMIDEs, at 50 ℃ of heated and stirred 24h, vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (40: 1), obtains 3.6 grams of N-{[2-(((4-cyano group-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (intermediate 9b).
3.6 grams of intermediate 9b are dissolved in 100mL ethanol, are cooled to 0 ℃, logical anhydrous hydrogen chloride gas 2h, then stirring at room 5h.By solvent evaporated in vacuo, then residue is dissolved in to 100mL ethanol, add 10 grams of volatile salts, stirred overnight at room temperature.By reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1), obtains 2.6 grams of target compound II
3.
1H?NMRδ(ppm，DMSO-d
6)：0.92(t，3H)，1.29(m，2H)，2.68(t，2H)，3.78(s，3H)，4.02(t，2H)，4.23(t，2H)，4.67(d，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(dt，1H)，7.82(d，2H)，8.42(dd，1H)，8.55-9.28(bs，3H)。
Reference example 4 N-{[2-(((the own oxygen carbonyl-amidino groups-phenyl of 4-N-)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl } preparation of-N-(pyridine-2-yl)-Beta-alanine ethyl ester (dabigatran dibasic acid esters)
By 2.0g (3.72mmol) N-{[2-(((4-amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (II
1) be dissolved in the solvent mixture of 100mL tetrahydrofuran (THF) and 20mL water, add 1.66g salt of wormwood (12mmol), stirring at room 20min.Add the n-hexyl chloride manthanoate of 0.62g (3.72mmol), continue to stir 2h.Vacuum is steamed and is desolventized, and adds 100ml saturated brine, uses dichloromethane extraction 3 times, 40ml/ time; United extraction liquid, with anhydrous sodium sulfate drying; Vacuum is steamed and is desolventized, and residue is separated with silica gel column chromatography, uses methylene dichloride: ethanol (95: 5) wash-out, obtains target compound 1.4g, mp 128-130 ℃.
1H?NMRδ(ppm，DMSO-d
6)：0.89(t，3H)，1.16(t，3H)，1.31(m，6H)，1.60(m，2H)，2.71(t，2H)，3.79(s，3H)，3.98(m，?4H)，4.25(t，2H)，4.62(d，2H)，6.75(d，2H)，6.90(d，1H)，6.97(t，1H)，7.14(m，2H)，7.41(d，1H)，7.49(d，1H)，7.56(m，1H)，7.82(d，2H)，8.41(dd，1H)，8.50-9.30(bs，2H)。
Work as R
3for C
1-C
8alkyl time, the synthetic route of target compound is as follows:
The carboxylates derivatives II of dabigatran reacts with carboxylic acid chloromethyl ester III, obtains target compound.
Embodiment 1 N-{[2-(((4-(N-propionyl oxygen methyl-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
18) preparation
By 0.65 gram of (1.3mmol) dabigatran ethyl ester (II
1) be dissolved in 2mL DMF, add 0.18 gram of K
2cO
3(1.3mmol), stir the lower 0.15mL (1.3mmol) of dropping chloromethyl propionic ester in the solution of 1mLDMF, in 15min, add; After adding, reaction mixture is reacted to 20h in stirring at room.By reaction solution vacuum concentration, residue is separated with silica gel column chromatography, use methylene dichloride: the mixed solvent wash-out of methyl alcohol (5: 1), obtains 0.48 gram of target compound I
18.
1H?NMRδ(ppm，DMSO-d
6)：1.08(t，3H)，1.14(t，3H)，2.34(q，2H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，5.75(s，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(dt，1H)，7.82(d，2H)，8.42(dd，1H)，8.58-9.30(bs，2H)。
Embodiment 2 N-{[2-(((4-(N-butyroxymethyl-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
19) preparation
With reference to the method for embodiment 1, with chloromethyl-butyric ester, replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make target compound I
19, productive rate 62%.
1H?NMRδ(ppm，DMSO-d
6)：0.85(t，3H)，1.14(t，3H)，1.51(m，2H)，2.28(t，2H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，5.75(s，2H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(dt，1H)，7.82(d，2H)，8.42(dd，1H)，8.58-9.30(bs，2H)。
Embodiment 3 N-{[2-(((4-(N-isobutyl acyl-oxygen methyl-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
20) preparation
With reference to the method for embodiment 1, with chloromethyl-isobutyrate, replace chloromethyl propionic ester to react with dabigatran ethyl ester (II1), make target compound I
20, productive rate 71%.
1H?NMRδ(ppm，DMSO-d
6)：1.05(d，6H)，1.14(t，3H)，2.55(m，1H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，5.75(s，2H)，6.89(m，3H)，7.12(m，2H)，7.36-7.60(m，4H)，7.68(d，2H)，8.41(m，1H)，8.68(s，2H)，8.58-9.30(bs，2H)。
Embodiment 4 N-{[2-(((4-(N-1-(butyryl acyloxy-) ethyl-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
67) preparation
With reference to the method for embodiment 1, with 1-chloroethyl-butyric ester, replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make target compound I
67, productive rate 68%.
1H?NMRδ(ppm，DMSO-d
6)：0.84(t，3H)；1.14(t，3H)，1.51(m，2H)，1.69(d，3H)，2.26(t，2H)，2.69(t，2H)，3.78(s，3H)，3.99(q，2H)，4.24(t，2H)，4.68(d，2H)，6.67(q，1H)，6.90(d，1H)，6.99(t，1H)，7.15(m，2H)，7.42(d，1H)，7.49(d，1H)，7.56(dt，1H)，7.82(d，2H)，8.42(dd，1H)，8.58-9.30(bs，2H)。
Work as R
3represent that alpha-position is amino alkyl or the aromatic alkyl (R replacing
3=-CH (NH2) R
4) time, the synthetic route of target compound following (in reaction formula, R
1represent methylidene, ethyl or propyl group, R
4represent the amino acid whose side chains of L-such as hydrogen, methyl, sec.-propyl, isobutyl-, 2-methyl-propyl or phenmethyl.)：
Bromochloromethane and chlorsulfonic acid reflux, obtain chloromethyl chlorsulfonic acid ester IV, and then IV reacts with N-tertbutyloxycarbonyl-amino acid, obtains the chloromethyl ester V of N-t-butoxycarbonyl amino acid, and V reacts with II and obtains intermediate VI, and VI deprotection obtains target compound.
Embodiment 5 N-{[2-(((4-(N-(L-glycyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
26) preparation
Synthesizing of 5.1 chloroformic acid chlorsulfonic acid esters (IV)
100mL chlorsulfonic acid is mixed with 50mL methyl chloride, be slowly heated to reflux, keep back flow reaction 3h.After cooling, slowly fall in 500 grams of trash ices.With dichloromethane extraction 2 times, 400mL/ time; Merge organic layer, with anhydrous sodium sulfate drying; Elimination siccative, steaming desolventizes, and then by resistates vacuum fractionation, collects the cut of 45-50 ℃/9-10mmHg, obtains 31 grams of product IV.
5.2 N-Boc-L-glycine-chloromethyl ester (V1) is synthetic
By 3.5 grams of (0.02mol) N-Boc-L-glycine, 6.65 grams of sodium bicarbonates and 0.68 gram of four-normal-butyl monoammonium sulfate (0.002mol) are added in the mixed solvent of 80ml water and 80ml methylene dichloride, cryosel is bathed and is cooled to O ℃, is slowly added dropwise to 4 grams of chloromethyl chlorsulfonic acid esters in the solution of 18ml methylene dichloride under vigorous stirring; After adding, rise to room temperature, continue stirring reaction 12 hours.Organic layer is separated, with saturated common salt washing 2 times, 15ml/ time; By organic layer anhydrous sodium sulfate drying, filtering siccative, filtrate decompression is concentrated, and residue is separated with silica gel column chromatography, uses sherwood oil: ethyl acetate (15: 1) wash-out, obtains V
13.2 grams of colorless oil.
5.3 N-{[2-(((4-(N-(N-Boc-L-glycyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1 methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (VI
1) preparation
With reference to the method for embodiment 1, with N-Boc-L-glycine-chloromethyl ester (V
1) replacement chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make VI
1, productive rate 68%.
5.4 N-{[2-(((4-(N-(L-glycyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
26) preparation
By 2.0 grams of VI
1with the dry Isosorbide-5-Nitrae of 10ml-dioxane, dissolve, under nitrogen protection, with cryosel, bathe and be cooled to 0 ℃, stir the lower 5ml that slowly drips containing the Isosorbide-5-Nitrae-dioxane solution of 15% hydrogenchloride, 0 ℃ of stirring reaction 1 hour, then in room temperature reaction 3 hours.Filter, with ether washing, obtain I
261.39g.Proton nmr spectra δ (ppm, DMSO-d
6): 1.14 (t, 3H), 2.69 (t, 2H), 3.78 (s, 3H), 3.85 (s, 2H), 3.99 (q, 2H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 6N-{[2-(((4-(N-(L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
27) preparation
With reference to the method for embodiment 5.2, with N-Boc-L-L-Ala, replace N-Boc-L-glycine, react with chloromethyl chlorsulfonic acid ester (IV), make N-Boc-L-L-Ala-chloromethyl ester (V
2), productive rate 57%.
With reference to the method for embodiment 1, use V
2replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make N-{[2-(((4-(N-(N-Boc-L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (VI
2), productive rate 52%.
With reference to the method for embodiment 5.4, by VI
2deprotection, obtains target compound I
27, productive rate 79%.Proton nmr spectra δ (ppm, DMSO-d
6): 1.14 (t, 3H), 1.52 (d, 3H), 2.69 (t, 2H), 3.78 (s, 3H), 3.99 (q, 2H), 4.24 (t, 2H), 4.35 (q, 1H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 7 N-{[2-(((4-(N-(L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
28) preparation
With reference to the method for embodiment 5.2, with N-Boc-L-leucine in place N-Boc-L-glycine, react with chloromethyl chlorsulfonic acid ester (IV), make N-Boc-L-leucine-chloromethyl ester (V
3), productive rate 59%.
With reference to the method for embodiment 1, use V
3replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make N-{[2-(((4-(N-(N-Boc-L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (VI
3), productive rate 47%.
With reference to the method for embodiment 5.4, by VI
3deprotection, obtains target compound I
28, productive rate 81%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.92 (d, 6H), 1.14 (t, 3H), 1.39 (m, 1H), 2.01 (q, 2H), 2.69 (t, 2H), 3.78 (s, 3H), 3.92 (t, 1H), 3.99 (q, 2H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 8 N-{[2-(((4-(N-(L-isoleucyl-oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
29) preparation
With reference to the method for embodiment 5.2, with N-Boc-L-Isoleucine, replace N-Boc-L-glycine, react with chloromethyl chlorsulfonic acid ester (IV), make N-Boc-L-Isoleucine-chloromethyl ester (V
4), productive rate 50%.
With reference to the method for embodiment 1, use V
4replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make N-{[2-(((4-(N-(N-Boc-L-isoleucyl-oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester VI
4), productive rate 61%.
With reference to the method for embodiment 5.4, by VI
4deprotection, obtains target compound I
29, productive rate 82%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.95 (t, 3H), 0.98 (d, 3H), 1.14 (t, 3H), 1.24 (m, 2H), 2.19 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 3.99 (q, 2H), 4.21 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 9 N-{[2-(((4-(N-(L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
30) preparation
With reference to the method for embodiment 5.2, with N-Boc-L-α-amino-isovaleric acid, replace N-Boc-L-glycine, react with chloromethyl chlorsulfonic acid ester (IV), make N-Boc-L-α-amino-isovaleric acid-chloromethyl ester (V
5), productive rate 54%.
With reference to the method for embodiment 1, use V
5replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make N-{[2-(((4-(N-(N-Boc-L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (VI
5), productive rate 49%.
With reference to the method for embodiment 5.4, by VI
5deprotection, obtains target compound I
30, productive rate 85%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.96 (d, 6H), 1.14 (t, 3H), 2.32 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 3.99 (q, 2H), 4.20 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 10 N-{[2-(((4-(N-(L-phenylalanyl oxygen methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (I
31) preparation
With reference to the method for embodiment 5.2, with N-Boc-L-phenylalanine, replace N-Boc-L-glycine, react with chloromethyl chlorsulfonic acid ester (IV), make N-Boc-L-phenylalanine-chloromethyl ester (V
6), productive rate 58%.
With reference to the method for embodiment 1, use V
6replace chloromethyl propionic ester and dabigatran ethyl ester (II
1) reaction, make N-{[2-(((4-(N-(N-Boc-L-phenylalanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine ethyl ester (VI
6), productive rate 46%.
With reference to the method for embodiment 5.4, by VI
6deprotection, obtains target compound I
31, productive rate 77%.Proton nmr spectra δ (ppm, DMSO-d
6): 1.14 (t, 3H), 2.69 (t, 2H), 3.13 (d, 2H), 3.78 (s, 3H), 3.99 (q, 2H), 4.22 (t, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.11-7.30 (m, 7H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 11 N-{[2-(((4-(N-isobutyryl acyl-oxygen methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (I
4) preparation
With reference to the method for embodiment 1, with isobutyryl chloride methyl ester (V
2) and dabigatran methyl esters (II
2) reaction, make target compound I
4, productive rate 55%.Proton nmr spectra
1h NMR δ (ppm, DMSO-d
6): 1.03 (d, 6H), 2.52 (m, 1H), 2.68 (t, 2H), 3.76 (s, 3H), 3.86 (s, 3H), 4.24 (t, 2H), 4.67 (d, 2H), 5.73 (s, 2H), 6.88 (m, 3H), 7.10 (m, 2H), 7.36-7.60 (m, 4H), 7.68 (d, 2H), 8.41 (m, 1H), 8.68 (s, 2H), 8.58-9.30 (bs, 2H).
Embodiment 12 N-{[2-(((4-(N-(L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (I
11) preparation
With reference to the method for embodiment 1, with N-Boc-L-L-Ala-chloromethyl ester (V
2) and dabigatran methyl esters (II
2) reaction, make N-{[2-(((4-(N-(N-Boc-L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (VI7), productive rate 52%.
With reference to the method for embodiment 5.4, by VI
7deprotection, obtains target compound I
11, productive rate 79%.Proton nmr spectra δ (ppm, DMSO-d
6) 1.52 (d, 3H), 2.69 (t, 2H), 3.78 (s, 3H), 3.89 (s, 3H), 4.24 (t, 2H), 4.35 (q, 1H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (
Embodiment 13 N-{[2-(((4-(N-(L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (I
12) preparation
With reference to the method for embodiment 1, with N-Boc-L-leucine-chloromethyl ester (V
3) and dabigatran methyl esters (II
2) reaction, make N-{[2-(((4-(N-(N-Boc-L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (VI
8), productive rate 47%.
With reference to the method for embodiment 5.4, by VI
8deprotection, obtains target compound I
12, productive rate 81%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.92 (d, 6H), 1.39 (m, 1H), 2.01 (q, 2H), 2.69 (t, 2H), 3.78 (s, 3H), 3.88 (s, 3H), 3.92 (t, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 14 N-{[2-(((4-(N-(L-isoleucyl-oxygen methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (I
13) preparation
With reference to the method for embodiment 1, with N-Boc-L-Isoleucine-chloromethyl ester (V
4) and dabigatran methyl esters (II
2) reaction, make N-{[2-(((4-(N-(N-Boc-L-isoleucyl-oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (VI
9), productive rate 61%.
With reference to the method for embodiment 5.4, by VI
9deprotection, obtains target compound I
13, productive rate 82%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.95 (t, 3H), 0.98 (d, 3H), 1.24 (m, 2H), 2.19 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 3.87 (s, 3H), 4.21 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 15 N-{[2-(((4-(N-(L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (I
14) preparation
With reference to the method for embodiment 1, with N-Boc-L-α-amino-isovaleric acid-chloromethyl ester (V
5) and dabigatran methyl esters (II
1) reaction, make target compound N-{[2-(((4-(N-(N-Boc-L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine methyl esters (VI
10), productive rate 49%.
With reference to the method for embodiment 5.4, by VI
10deprotection, obtains target compound I
14, productive rate 85%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.96 (d, 6H), 2.32 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 3.90 (s, 3H), 4.20 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 16 N-{[2-(((4-(N-(L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (I
43) preparation
With reference to the method for embodiment 1, with N-Boc-L-L-Ala-chloromethyl ester (V
2) and dabigatran propyl ester (II
3) reaction, make N-{[2-(((4-(N-(N-Boc-L-alanyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (VI11), productive rate 52%.
With reference to the method for embodiment 5.4, by VI
11deprotection, obtains target compound I
43, productive rate 79%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.92 (t, 3H), 1.29 (m, 2H), 1.52 (d, 3H), 2.69 (t, 2H), 3.78 (s, 3H), 4.02 (t, 2H), 4.24 (t, 2H), 4.35 (q, 1H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 17 N-{[2-(((4-(N-(L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (I
44) preparation
With reference to the method for embodiment 1, with N-Boc-L-leucine-chloromethyl ester (V
3) and dabigatran propyl ester (II
3) reaction, make N-{[2-(((4-(N-(N-Boc-L-leucyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (VI
12), productive rate 47%.
With reference to the method for embodiment 5.4, by VI
12deprotection, obtains target compound I
44, productive rate 81%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.90-0.92 (m, 9H), 1.29 (m, 2H), 1.39 (m, 1H), 2.01 (q, 2H), 2.69 (t, 2H), 3.78 (s, 3H), 3.92 (t, 1H), 4.02 (t, 2H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 18 N-{[2-(((4-(N-(L-isoleucyl-oxygen methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (I
45) preparation
With reference to the method for embodiment 1, with N-Boc-L-Isoleucine-chloromethyl ester (V
4) and dabigatran propyl ester (II
3) reaction, make target compound N-{[2-(((4-(N-(N-Boc-L-isoleucyl-oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (VI
13), productive rate 61%.
With reference to the method for embodiment 5.4, by VI
13deprotection, obtains target compound I
45, productive rate 82%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.92 (t, 3H), 0.95 (t, 3H), 0.98 (d, 3H), 1.24 (m, 2H), 1.29 (m, 2H), 2.19 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 4.02 (t, 2H), 4.21 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
Embodiment 19 N-{[2-(((4-(N-(L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (I
46) preparation
With reference to the method for embodiment 1, with N-Boc-L-α-amino-isovaleric acid-chloromethyl ester (V
5) and dabigatran propyl ester (II
3) reaction, make target compound N-{[2-(((4-(N-(N-Boc-L-valyl oxygen-methyl)-) amidino groups-phenyl)-amino)-methyl)-1-methyl isophthalic acid H-benzoglyoxaline-5-yl]-carbonyl }-N-(pyridine-2-yl)-Beta-alanine propyl ester (VI
14), productive rate 49%.
With reference to the method for embodiment 5.4, by VI
14deprotection, obtains target compound I
46, productive rate 85%.Proton nmr spectra δ (ppm, DMSO-d
6): 0.92 (t, 3H), 0.96 (d, 6H), 1.29 (m, 2H), 2.32 (m, 1H), 2.69 (t, 2H), 3.78 (s, 3H), 4.02 (t, 2H), 4.20 (d, 1H), 4.24 (t, 2H), 4.68 (d, 2H), 5.85 (s, 2H); 6.90 (d, 1H), 6.99 (t, 1H), 7.15 (m, 2H), 7.42 (d, 1H), 7.49 (d, 1H), 7.56 (m, 1H), 7.82 (d, 2H), 8.42 (dd, 1H), 8.55-9.28 (bs, 5H).
The evaluation of embodiment 20 anticoagulating actives
The mensuration of 20.1 activated partial thromboplastin times (aPTT)
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, by the dosage of 10mg/kg (amounting to into dabigatran calculates) gastric infusion, after half an hour, pass through heart puncturing extracting blood, add 4% liquor sodii citratis to 0.4% final concentration anti-freezing, centrifugal 5 minutes of 12000r/min, get blood plasma 0.1ml, add aPTT reagent (Shanghai medical electric company limited product) 0.1ml, 37 ℃ of pre-temperature are after 3 minutes, the calcium chloride solution 0.1mL that adds 37 ℃ of pre-temperature, with platelet aggregation thrombin analyser (the raw PLSC2000-4 type of Puli), measure setting time, be aPTT value.The results are shown in Table 1.
The measurement result of table 1 activated partial thromboplastin time (aPTT)
The mensuration in 20.2 bleeding times
By the kunming mice of quality 18-20g, random packet, 10 every group, overnight fasting.Dabigatran etcxilate (Dabigatran Etexilate) and target compound to be measured are suspended or be dissolved in the aqueous solution of 1% Xylo-Mucine, be made into the concentration of 1mg/ml, by the dosage of 10mg/kg (amounting to into dabigatran calculates) gastric infusion, after half an hour.Animal is fixed, make tail be dipped in 2min in the physiological saline of 37 ℃, then apart from tail end 2mm place, cutting off mouse tail, again immerse immediately in the physiological saline of 37 ℃, take and stop hemorrhagely continuing 30 seconds as judgement terminal, measure the bleeding time.The results are shown in Table 2.
The measurement result in table 2 bleeding time (aPTT)
Claims (6)
1. the ester derivative of the dabigatran shown in formula I or its pharmacy acceptable salt:
Wherein,
R
1represent H or C
1-C
5alkyl; R
2represent H, or C
1-C
3alkyl;
R
3represent C
1-C
8alkyl or alpha-position be the amino C replacing
1-C
8alkyl.
2. the ester derivative of the dabigatran of the formula I representative of claim 1 or its pharmacologically acceptable salt, wherein R
1represent C
1-C
5alkyl, R
2represent H or C
1-C
3alkyl, R
3represent C
1-C
8alkyl.
3. the ester derivative of the dabigatran of the formula I representative of claim 1 or its pharmacologically acceptable salt, wherein R
1represent C
1-C
5alkyl, R
2represent H, R
3represent that alpha-position is the amino C replacing
1-C
8alkyl.
4. the ester derivative of the dabigatran of formula I representative claimed in claim 1 or its pharmacologically acceptable salt, be selected from the compound of following structural formula representative:
Wherein, R
1, R
2and R
3be defined as follows respectively:
I4:R
1for-CH
3, R
2for H, R
3for-CH (CH
3)
2;
I
11: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
12: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
13: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
14: R
1for-CH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
18: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
3;
I
19: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2cH
2cH
3;
I
20: R
1for-CH
2cH
3, R
2for H, R
3for-CH (CH
3)
2;
I
26: R
1for-CH
2cH
3, R
2for H, R
3for-CH
2nH
2;
I
27: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
28: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
29: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
30: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
31: R
1for-CH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2ph;
I
43: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
3;
I
44: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH
2cH (CH
3)
2;
I
45: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3) CH
2cH
3;
I
46: R
1for-CH
2cH
2cH
3, R
2for H, R
3for-CH (NH
2) CH (CH
3)
2;
I
67: R
1for-CH
2cH
3, R
2for CH
3, R
3for-CH
2cH
2cH
3.
5. pharmaceutical composition, it comprises ester derivative or its pharmacologically acceptable salt of the dabigatran described at least one claim 1-4 any one, and one or more pharmaceutically acceptable carrier or vehicle.
6. the ester derivative of the dabigatran described in claim 1-4 any one or its pharmacologically acceptable salt, and the ester derivative that contains the dabigatran described in claim 1-4 any one or its pharmacologically acceptable salt as the pharmaceutical composition of activeconstituents the purposes in preparing thrombin inhibitors medicine.
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